1. Field of the Invention
The invention relates to the use of adenosine antagonists, either alone or in combination with pharmacologic agents possessing and/or -adrenergic or dopaminergic properties, to treat cardiac rhythm disturbances, mechanical dysfunction and hypotension and to facilitate cardioversion and/or defibrillation in the setting of cardiopulmonary resuscitation.
2. Discussion of the Background
Prolonged cardiopulmonary resuscitation for ventricular fibrillation is associated with the occurrence of asystole or severe bradycardias and profound hemodynamic collapse associated with a severe depression in myocardial contractility (electro-mechanical dissociation) which are usually resistant to therapy. (Rahimtoola S. H., J. Am. Med. Assoc., 247, pages 2485-2890 (1982) and Iseri, L. T., Ann. Int. Med., 88, pages 741-745 (1978).)
Catecholamines and/or para-sympatholytic agents have traditionally been used to treat intractable ventricular fibrillation and post-defibrillation depressions in automaticity, cardiac conduction, and overall hemodynamic collapse. However, these agents are often ineffective, particularly in the setting of prolonged ventricular fibrillation and, as a consequence of their use, may provoke intractable ventricular fibrillation followed by death or severe neurological impairment. See McIntyre, K. M., Lewis, A. J., Eds, Textbook of Advanced Life Support, Vol 9, American Heart Association (1981) and Am. Heart J., 97, 225-228 (1979).
Pharmacological agents are routinely used in the cardiopulmonary resuscitation of patients suffering from cardiac arrest. A review of these pharmacologic agents can be found in Otto C. W., Circ. 74 (supplement IV), IV-80-85 (December 1986). It has been established that the most significant factor in the return of spontaneous circulation during cardiopulmonary resuscitation is the enhancement of .alpha.-adrenergic tone, i.e., an increase in aortic diastolic pressure and coronary perfusion pressure. However, there has been no suggestion that the use of .alpha.-adrenergic agents improve survival relative to the use of epinephrine, a mixed adrenergic agonist with known deleterious effects.
Additionally, there is no clear evidence that epinephrine, the currently recommended pharmacologic agent, can increase the effectiveness of electric shock during the fibrillation.
Lidocaine is the recommended anti-arrhythmic agent for use during cardiac arrest. It is known however that lidocaine can increase the threshhold for defibrillation. Under experimental conditions, the anti-arrhythmic drug, Bretylium, seems to facilitate defibrillation; however, clinical data are less convincing. (Jaffe A. S., Circ. 74 (supplement IV), IV-70-74, December 1986).
The model established by the present inventors confirms that the cardioversion of prolonged hypoxic ventricular fibrillation is accompanied by cardiovascular collapse and depressions in cardiac automaticity, conduction, and contractility. This post-shock hypoxic depression is due, in part, to the collapse in arteriolar tone possibly mediated by the release of endogenous adenosine. In addition, the release of endogenous adenosine from myocardium might selectively dilate coronary resistance vessels promoting hypoperfusion of the subendocardial layer of the heart, the most distal and thus vulnerable cardiac vascular bed. The result would be enhanced ischemic-induced depression in contractility. Endogenous catecholamines are known to be released with vascular collapse and perhaps in response to an electrical shock. The beneficial vasomotor and inotropic effects of endogenous catecholamine release may, in turn, be attenuated by the anti-adrenergic action of endogenous adenosine. The aforementioned potential deleterious effects of endogenous adenosine may be reversed by adenosine antagonism. Thus, adenosine antagonism represents an important new therapy in the amelioration of the overall hemodynamic state during cardiopulmonary resuscitation and following defibrillation and, thus, would be expected to enhance survival of cardiac arrest victims. This concept has never been proposed.
It is known that endogenous adenosine can depress the electrical conduction through the atrioventricular (A-V) node, and that adenosine antagonism can reverse this phenomenom. U.S. Pat. No. 4,364,922 discloses a method of treating atrioventricular conduction block using adenosine antagonists. However, A-V conduction disturbances play only a small role in the overall constellation of factors which characterize bradyasystolic arrest. The more predominant factors noted in the clinical sector include profound bradycardia associated with junctional and ventricular escape rhythms, and hemodynamic depression secondary to vascular collapse and severe inotropic dysfunction (see Iseri, L. T. et al, loc cit). The use of adenosine antagonism to reverse these phenomena in the setting of prolonged cardiopulmonary resuscitation has never been proposed.
Accordingly, there exists a need for a more effective pharmacologic method of treating the bradyarrhythmias associated with prolonged cardiopulmonary resuscitation. In addition, there exists a further need for a method of treating these arrhythmias which does not evolve into intractible ventricular fibrillation.
In addition to the aforementioned, the inventors have found that adenosine antagonism lowers the threshold current required for defibrillation and thereby increases the effectiveness of electric shock therapy. Thus, an intravenously administered form of adenosine antagonism may be important in reducing the duration of ventricular fibrillation, a prognostic factor known to enhance survival in the setting of cardiac arrest and resuscitation. In addition, an orally administered and longer-acting form of adenosine antagonism may be important in lowering the energy and current requirements of shock therapy administered by implanted electrodes, increase the efficacy of electric shock, and reduce the energy load on devices thus extending the device's battery life and battery replacement schedule. Adenosine antagonism may also lower the threshold current for cardiac pacing via endocardial and epicardial electrode placement or via transthoracic pacing electrodes. In addition to intravenous and oral forms, a local sustained release form of adenosine antagonist may be incorporated into the electrode tips of endocardial and epicardial leads for the purpose of lowering pacing thresholds.
At present there are no claims in the medical literature divulging the use of adenosine antagonism to lower energy and current requirements for cardioversion, defibrillation, and cardiac pacing. Kralios et al (Am Heart J: 105(4): 580-586) infused exogenous adenosine into canine coronary arteries and demonstrated a reduction in the threshold current necessary to induce ventricular fibrillation. However, the authors conclude "physiologic or pharmacologic coronary vasodilation without evidence of concomitant myocardial hypoxia" may contribute to the electrical instability resulting in ventricular fibrillation. No claim was made that the release of endogenous adenosine during the conditions of anoxia or hypoxia mediated such electrical instability or that antagonism of endogenously released adenosine would promote ventricular defibrillation. Ruffy et al (J. Am. Coll. Cardiology 9(2): 142A, 1987) showed that aminophylline (10 mg/Kg IV) lowered defibrillation threshold in conscious dogs. Aminophylline is a relatively weak adenosine antagonist with well established effects on phosphodiesterase inhibition. The authors did not correlate effects on defibrillation threshold with serum levels of aminophylline. At a dose of 10 mg/Kg, the authors could not and did not claim that the effect of aminophylline was mediated via adenosine antagonism.
Additionally, the inventors have demonstrated in a pentobarbital anesthetized dog that 8-phenylsulfonyltheophylline (8-PST) (5 mg/Kg IV) lowered the peak threshold current for defibrillation of VF lasting 1 minute from 16.6A to 13.1A with a rise to 15.1A during a wash-out period. In contrast to aminophylline, 8-PST is highly specific for competitive adenosine antagonism and causes no significant inhibition of phosphodiesterase activity (Clemo, S. H. F. and L. Belardinelli, 1985). A comparative study of antagonism by alkylxanthines on the negative dromotropic effect of adenosine and hypoxia in isolated guinea-pig hearts is disclosed in Current Clinical Practice Series No. 19: Anti-asthma Xanthines and Adenosine, K. E. Anderson and C. Kong, Princeton, Sydney, Tokyo, pp. 417-422; and F. W. Smellie, C. W. Davis, J. W. Daly, and J. N. Wells, 1979. Alkylxanthine inhibition of adenosine-elicited accumulation of cyclic AMP in brain slices and of brain phosphodiesterase activity is disclosed in Life Sci. 24:2475-2482. Thus, we claim that the observed effect is mediated by adenosine antagonism and is consistent with our other experimental observations. Since no convincing clinical data exist establishing the efficacy of presently available pharmacologic agents in reducing threshold currents for defibrillation, we propose that there exists a need for such an agent.